Changes in genetic variant results over time in pediatric cardiomyopathy and electrophysiology

Abstract

Genetic testing for cardiac disorders continues to change. Our objective was to assess trends in variant classification in pediatric arrhythmia and cardiomyopathy. We conducted a retrospective review of patients tested for genetic arrhythmia and cardiomyopathy disorders from 2006–2017. Variants were classified by CLIA laboratories. Trends were assessed by the Spearman correlation. There were 914 variants in 583 patients from 337 families. The total number of tests ordered increased over time, accelerating after 2012. There was a strong positive correlation between the average number of genes tested per panel and year of testing (r = .97, p < .001) and a weak correlation between the year and a decrease in the percentage of clinically actionable variants (r = −.20, p = .005). By 2011, VUS represented >50% of variants reported on panels. Over 12 years, 203 genes were interrogated; one or more variants were reported in 91 of 203 genes (45%). 32% of patients had at least one clinically actionable variant; 28% had at least one VUS. Reclassification is an important long‐term issue, with 21.5% variants changing clinical interpretation. We observed an increase over time in three areas: total number of tests ordered, average number of genes/panel, and percentage of VUS. Providers may need to interpret results from 90 + genes, and ongoing education is critical. Due to their specific training in test result interpretation, we recommend the inclusion of a genetic counselor in pediatric electrophysiology and cardiomyopathy teams.

Clinical impact of rare variants associated with inherited channelopathies: a 5-year update

“…In another study, reclassification after 7 years (from 2011 to 2018) increased the molecular diagnosis of ICC by 2% in cases of unexpected decease (Salfati et al 2019). In an additional cohort analyzed for genetic arrhythmia and cardiomyopathy disorders from 2006 to 2017, 22% of variants changed classification and approximately 10% changed in a way that altered clinical interpretation (Cherny et al 2020). Following similar results, VanDyke et al published that 35% of the variants associated with ICC had classifications that differed from their firsts reports (all prior 2015) (VanDyke et al 2020).…”

“…Other data, e.g., functional studies, may corroborate the pathogenic role of a rare variant (Glazer et al 2020), but unfortunately, a complete family segregation as well as functional analysis are not available for most rare variants currently associated with ICC. It is also important to note that a low percentage of current VUS may eventually be shown to confer a real risk of ICC (Blekhman et al 2008); however, distinguishing pathogenic VUS from the majority of VUS is one of the main current challenges in the ICC field (Cherny et al 2020;Tsai et al 2019).…”

Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy

“…This is consistent with data previously published in pediatric cardiology, demonstrating the long‐term value in a centralized program with access to genetic counseling and variant re‐adjudication. 24 Finally, the 2015 American College of Medical Genetics guidelines improved variant adjudication, but did not make it entirely uniform. We found differences between our clinical adjudication and the classifications made by an independent laboratory.…”

Integrating clinical genetics in cardiology: Current practices and recommendations for education

“… 24 An article examining recent changes in pediatric cardiovascular genetics found that the increased use of panel testing, which includes a greater number of genes associated with cardiovascular conditions, has increased the complexity of genetic testing and result interpretation, thus leading to the recommendation of including genetic counselors in pediatric electrophysiology and cardiomyopathy teams. 25 To summarize, involving a genetic counselor in cardiology practice can facilitate appropriate test selection, facilitate identification of the best person in a family to test, provide accurate result interpretation, and facilitate effective communication with the patient and their family, which ultimately can reduce health care costs. 26 …”